Glycolipid Antigen Processing for Presentation by CD1d Molecules

Prigozy, Theodore I.; Naidenko, Olga V.; Qasba, Pankaj; Elewaut, Dirk; Brossay, Laurent; Khurana, Archana; Natori, Takenori; Koezuka, Yasuhiko; Kulkarni, Ashok B.; Kronenberg, Mitchell

doi:10.1126/science.291.5504.664

Cited by 277 publications

(286 citation statements)

References 23 publications

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“…3), showing that some amount of processing is required for the presentation of these bacterial lipids. These results are in accordance with those shown by Prigozy et al [16], and imply that GSL with more than one carbohydrate moiety attached to the ceramide bind to cell surface CD1d, but are endocytosed and processed to a simple GSL before being presented to NKT cells. The anti-mouse-CD1d monoclonal antibody 1H6 [17] (but not the negative control Ab) completely blocked the bacterial GSL presentation to NKT cells, confirming the CD1d-dependence of GSL recognition (Fig.…”

Section: Resultssupporting

confidence: 92%

“…Our results support this observation. The fact that NKT cell stimulation is not dependent upon the anomericity of the outermost sugar residues, as long as the inner core sugar attachment to ceramide is in an aorientation, makes GSL-4A a candidate ligand for CD1d that may require further processing before its presentation [4,16].…”

Section: Discussionmentioning

confidence: 99%

“…These results suggest that there is a requirement for GSLantigen-processing or endosomal uptake and loading during the 3-h pulse period. It should be noted that pure a-GalCer has been shown to activate NKT cells in a CD1d-restricted manner without the need for any processing [4,14,16]. However, the lipid mixtures used in our experiments also contain a tetraglycosylated lipid (GSL-4A) along with the simple a-GlcUCer.…”

Section: Requirement Of Processing For the Presentation Of S Paucimomentioning

confidence: 99%

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Cell wall glycosphingolipids ofSphingomonas paucimobilisare CD1d-specific ligands for NKT cells

et al. 2005

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The current consensus on characterization of NKT cells is based on their reactivity to the synthetic glycolipid, a-galactosylceramide (a-GalCer) in a CD1d-dependent manner. Because of the limited availability of a-GalCer, there is a constant search for CD1d-presented ligands that activate NKT cells. The a-anomericity of the carbohydrate is considered to be an important requisite for the CD1d-specific activation of NKT cells. The gram-negative, lipopolysaccharide-free bacterium Sphingomonas paucimobilis is known to contain glycosphingolipids (GSL) with a-anomeric sugars attached to the lipid chain. Here, we report that GSL extracted from this bacterium are able to stimulate NKT cells in a CD1d-specific manner. In addition, soluble CD1d-Ig dimers loaded with this lipid extract specifically bind to NKT cells (but not conventional T cells). Further studies on the S. paucimobilis GSL could potentially lead to other natural sources of CD1d-specific ligands useful for NKT cell analyses and aimed at identifying novel therapies for a variety of disease states. IntroductionLipid antigens, including phospholipids and glycosphingolipids (GSL), are presented by CD1d -a subset of the CD1 family of MHC class I-like molecules -to specialized immune effector cells called NKT cells [1]. Located on a different chromosome than the MHC, five different CD1 genes encode CD1 molecules -CD1a, CD1b, CD1c, CD1d and CD1e -in humans, whereas only two homologues of CD1d (CD1d1 and CD1d2) are present in mice [2]. On the basis of the crystal structure of mouse CD1d1 [3], it is predicted that the fatty-acyl chains are buried in the hydrophobic pocket of the molecule with the hydrophilic head-group of the lipid antigen available outside the molecule for its interaction with the NKT cell receptor. Even though the lipidbinding groove of CD1d is widely accommodative of many lipid groups, it is believed that only the sugar structures in a-anomeric orientation are able to stimulate NKT cells [4]. Because of the lack of physiological glycolipids with terminal a-anomeric sugars, it is hypothesized that both altered selfglycolipids during a pathological process and exogenous antigenic glycolipids could be potential ligands presented by CD1d [4]. The presence of GSL in the cell wall of some bacterial strains indicates the possibility of these bacterial GSL being presented by CD1d. Although human CD1a, b and c molecules are known to present mycobacterial antigens to human NKT cells, there is a lack of substantial evidence to show that CD1d has the ability to present these microbial lipids [5]. In a recent study, Fischer et al. [6] were able to show that mycobacterial phosphoinositolmannosides (PIM) could bind to soluble CD1d and activate human and mouse NKT cells. However, only a fraction of NKT cells detected by agalactosylceramide (a-GalCer) could be stained by a CD1d tetramer loaded with mycobacterial PIM [6]. A recent study [7] was able to show the binding of synthetic a-GalNAc containing GSL to cell surface CD1d, but no functional studies were done t...

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Section: Resultssupporting

confidence: 92%

Section: Discussionmentioning

confidence: 99%

Section: Requirement Of Processing For the Presentation Of S Paucimomentioning

confidence: 99%

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Cell wall glycosphingolipids ofSphingomonas paucimobilisare CD1d-specific ligands for NKT cells

et al. 2005

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“…In mice, it was shown for some glycolipid antigens that terminal sugars were removed by specific glycosidases before CD1d loading was permitted [81], analogous to the system for glycopeptide antigen processing before presentation to T cells. Type I CD1 presents lipid antigens to T cells, which respond by polyclonal activation, suggesting a relatively wide range of specificities for antigen binding [83] In contrast, Type II CD1 molecules present lipids to Natural Killer T (NKT) cells with structurally more conserved T cell antigen receptors [84] In the early days following the discovery that human dendritic cells presented mycobacterial MA to T cell lines, it was believed that only CD4/CD8 double negative and CD8 positive T cells were responsive to the presented MA [85].…”

Section: Does Structure Matter?mentioning

confidence: 99%

Towards understanding the functional diversity of cell wall mycolic acids of Mycobacterium tuberculosis

Verschoor

Baird

Grooten

2012

Progress in Lipid Research

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Mycolic acids constitute the waxy layer of the outer cell wall of Mycobacterium spp and a few other genera. They are diverse in structure, providing a unique chromatographic foot-print for almost each of the more than seventy Mycobacterium species. Although mainly esterified to cell wall arabinogalactan, trehalose or glucose, some free mycolic acid is secreted during in vitro growth of M. tuberculosis. In M. tuberculosis, alpha-, keto-and methoxy-mycolic acids are the main classes, each differing in their ability to attract neutrophils, induce foamy macrophages or adopt an antigenic structure for antibody recognition. Of interest is their particular relationship to cholesterol, discovered by their ability to attract cholesterol, to bind Amphotericin B or to be recognised by monoclonal antibodies that cross-react with cholesterol. The structural elements that determine this diverse functionality include the carboxylic acid in the mycolic motif, as well as the nature and stereochemistry of the two functional groups in the merochain. The functional diversity of mycolic acid classes implies that much information may be contained in the selective expression and secretion of mycolic acids to establish tuberculosis after infection of the host. Their cholesteroid nature may relate to how they utilize host cholesterol for their persistent survival.

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“…Lipids with large hydrophilic moieties form antigenic complexes with CD1 molecules after partial degradation. The hydrolases a-galactosidase A, hexosaminidase B and acidic a-mannosidase are involved in partial degradation of glycolipid antigens [5,54,55], thus indicating that glycolipid processing takes advantage of different enzymes involved in lysosomal glycolipid degradation. Whether lipases contribute to lipid antigen processing is unknown.…”

Section: Lipid Antigen Processing and Loading On Cd1 Moleculesmentioning

confidence: 99%

The cellular and biochemical rules of lipid antigen presentation

2009

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The recognition of both protein and lipid antigens follows similar strategies that rely on different molecular mechanisms. APC present lipid antigens exploiting the same mechanisms implicated in lipid translocation, lipoprotein assembly and lipid degradation. An important issue is how the lipid structure contributes to antigenicity. Lipid hydrophobicity influences the modes of internalization by APC, the trafficking through different membrane compartments, the binding to CD1 molecules and the stability of antigenic complexes. Some glycolipids with large hydrophilic parts require processing of the sugar moieties exerted by lysosomal hydrolases. Finally, extraction of lipids from membranes, their solubilization and loading on CD1 molecules are facilitated by the same lysosomal lipid-binding proteins that are also instrumental in lipid catabolism. More recent investigations reveal how lipid-specific immunity is regulated during infections. In this review we describe the main cellular and biochemical rules of lipid antigen presentation and discuss their implications in anti-microbial and autoimmune responses.Key words: Antigen recognition . CD1 . Lipid antigens . TCR IntroductionMembers of the MHC or CD1 families present protein and lipid antigens to T cells, respectively. CD1 molecules are differentially expressed by a variety of cell types including DC, B cells, monocytes, Langerhans cells, stellate hepatic cells, epithelial cells, microglial cells and keratinocytes. In humans, five genes (CD1A, B, C, D and E) encode CD1 proteins. CD1a, CD1b, CD1c and CD1d molecules reach the plasma membrane and are involved in lipid presentation to T cells, whereas CD1e remains intracellular and is involved in lipid processing. Lipid-specific T cells express a variety of TCR heterodimers, with the exception of invariant NKT (iNKT) cells, a CD1d-restricted population that uses a semi-invariant TCR (invariant Va24-Ja18 and variable Vb11 chains in humans, invariant Va14-Ja18 and variable Vb8.2, Vb7 or Vb2 chains in mice).Proteins become antigenic after a series of events starting with partial degradation by the cellular machinery represented by the proteasome or by proteases located in lysosomes (Ly) and endoplasmic reticulum (ER). This immunological function, commonly known as antigen processing, leads to the generation of peptide fragments that are carried to the proximity of MHC molecules with which they form antigenic complexes. A similar scheme applies to the presentation of lipid antigens. Lipids derived from extracellular routes are internalized or alternatively, self-lipid antigens are synthesized within the APC. These lipids are then transported into the cellular compartments where CD1 molecules traffic and after loading onto CD1, form antigenic complexes.The physicochemical properties of lipids and peptides impose the utilization of different strategies by the APC to digest, transport and load each of these classes of molecules. Antigenicity of lipids is achieved with the participation of extracellular and intracellular li...

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Glycolipid Antigen Processing for Presentation by CD1d Molecules

Cited by 277 publications

References 23 publications

Cell wall glycosphingolipids ofSphingomonas paucimobilisare CD1d-specific ligands for NKT cells

Cell wall glycosphingolipids ofSphingomonas paucimobilisare CD1d-specific ligands for NKT cells

Towards understanding the functional diversity of cell wall mycolic acids of Mycobacterium tuberculosis

The cellular and biochemical rules of lipid antigen presentation

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